What is the mechanism of action (MOA) of isosorbide dinitrate (isosorbide dinitrate) in a patient with angina pectoris?

Mechanism of Action of Isosorbide Dinitrate in Angina Pectoris

Isosorbide dinitrate works by serving as an exogenous source of nitric oxide that relaxes vascular smooth muscle, primarily causing venodilation (preload reduction) with secondary arterial effects (afterload reduction) and coronary artery dilation, all of which reduce myocardial oxygen demand and improve oxygen supply. 1

Molecular Mechanism

• Isosorbide dinitrate undergoes enzymatic conversion (via glutathione S-transferase, cytochrome P-450, and possibly esterases) to release nitric oxide, which replenishes or restores the actions of endothelium-derived relaxing factor 2, 3
• The released nitric oxide stimulates soluble guanylate cyclase, increasing cyclic GMP production 3
• Cyclic GMP activates cGMP-dependent protein kinase, which ultimately lowers intracellular calcium through increased uptake into intracellular stores and decreased release 3
• This calcium reduction leads to vascular smooth muscle relaxation 3

Primary Hemodynamic Effects

Venodilation (Preload Reduction)

• The drug acts predominantly as a potent venodilator, dilating capacitance vessels and promoting peripheral pooling of blood 4, 2
• This decreases venous return to the heart, reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure 2, 1
• Echocardiographic studies demonstrate end-diastolic volume reductions of more than 30 ml that persist for up to four hours 5

Arterial Effects (Afterload Reduction)

• Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure 1
• These arterial effects are more prominent when systemic vascular resistance is severely elevated 6
• Mean arterial blood pressure reductions of 5 to 10 mm Hg persist for more than four hours following administration 5

Coronary Artery Dilation

• Direct coronary artery dilation occurs, improving oxygen supply to the myocardium 2, 7
• The relative importance of preload reduction, afterload reduction, and coronary dilation in the overall therapeutic effect remains undefined 2, 1

Net Effect on Myocardial Oxygen Balance

• The combined preload and afterload reduction decreases cardiac work and lowers myocardial oxygen requirements 8, 2
• This is particularly beneficial in angina pectoris where myocardial oxygen demand exceeds supply 2
• The drug addresses both sides of the oxygen supply-demand equation: reducing demand through hemodynamic effects while improving supply through coronary dilation 7, 3

Additional Mechanisms

• Inhibition of platelet aggregation occurs, which may contribute to therapeutic value 3
• Recent evidence suggests nitrates can inhibit abnormal myocardial and vascular growth, potentially attenuating ventricular remodeling 6

Pharmacokinetic Considerations for Clinical Effect

• The parent compound has a serum half-life of approximately one hour, but active metabolites (particularly the 5-mononitrate with a half-life of about 5 hours) contribute to a duration of action up to 8 hours with standard oral formulations 2, 1
• Bioavailability is highly variable (10% to 90%) due to extensive first-pass hepatic metabolism, with an average of about 25% 1
• The drug is metabolized primarily by denitration to 2-mononitrate (15-25%) and 5-mononitrate (75-85%), both of which have biological activity 1

Critical Clinical Caveat: Nitrate Tolerance

• Continuous therapy leads to tolerance development, with anti-anginal efficacy lost after 24 hours or less of continuous exposure 2, 1
• Only after nitrates have been absent from the body for several hours is their efficacy restored 1
• A nitrate-free interval of at least 10 hours (and preferably 14 hours for isosorbide dinitrate) is necessary to minimize tolerance development 6, 8, 1
• Combination with ACE inhibitors or hydralazine may help minimize tolerance development 6

Common Side Effects Related to Mechanism

• Headaches are the most common side effect, resulting from cerebral vasodilation 6, 4, 8
• Hypotension occurs due to the vasodilatory effects, which may trigger reflex tachycardia and potentially worsen myocardial ischemia 4, 8
• Dizziness related to blood pressure changes is another consequence of the vasodilatory mechanism 8